PL196516B1 - New 8-aryl-2H-3,4,6,7-tetrahydroimidazo [2,1-c] [1,2,4] triazine -4-oxo-3-acetic acid ethyl esters and their preparation - Google Patents

Abstract

1. New ethyl esters of 8-aryl-2H- -3,4,6,7-tetrahydroimidazo [2,1-c] [1,2,4] triazine-4-oxo-3-acetic acids of general formula 1 wherein R is an aromatic substituent, preferably 4-methylphenyl, 4-methoxyphenyl, 3-chloro-phenyl, 4-chlorophenyl.

Description

REPUBLIC

POLAND

Patent Office of the Republic of Poland (12) PATENT DESCRIPTION (19) PL (11) 196516 (13) B1 (21) Application number: 365355 ^{(51) Int.Cl.}

C07D 487/04 (2006.01) C07D 233/52 (2006.01) A61K 31/4985 (2006.01) (22) Date of filing: 18.02.2004 A61P 31/00 (2006.01)

New ethyl esters of 8-aryl-2H-3,4,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazine-4-oxo-3-acetic acids and a method for their preparation

(73) Patent holder: (43) The application was announced: Feliks Skubiszewski Medical University, Lublin, Poland 22/08/2005 BUP 17/05 (72) Inventor(s): Krzysztof Sztanke, Lublin, PL (45) The patent was granted on: 31/01/2008 WUP 01/08 (74) Attorney: Anna Bełz, Feliks Skubiszewski Medical University

⁽⁵⁷⁾ 1. New ethyl esters of 8-aryl-2H-3,4,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazine-4-oxo-3-acetic acids of the general formula 1, wherein R is an aromatic substituent, preferably 4-methylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl.

PL 196 516 B1

Description of the invention

The subject of the invention are new ethyl esters of 8-aryl-2H-3,4,6,7-tetrahydroimidazo-[2,1-c][1,2,4]triazine-4-oxo-3-acetic acids.

Previously known imidazo[2,1-c]triazine derivatives are obtained as cardiovascular agents, compounds with positive cardiac inotropic activity, central nervous system stimulants, herbicides, bactericides, and Maillard reaction inhibitors. The imidazo[2,1-c]triazine derivatives known from European Patent No. 531,812 are used to prevent chronic diabetic complications such as atherosclerosis, coronary artery disease, cerebrovascular disease, neuropathy, nephropathy, and cataracts.

The new ethyl esters of 8-aryl-2H-3,4,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazine-4-oxo-3-acetic acids of the general formula 1, where R is an aromatic substituent, preferably 4-methylphenyl, 4-methoxyphenyl, 3-chlorophenyl and 4-chlorophenyl, which are the subject of the invention, constitute a group of new compounds not described in the source literature so far.

Compounds of general formula 1, according to the invention are obtained by condensation of an appropriately substituted imidazolidine-2-one hydrazone hydrohalide, i.e. a compound of general formula 2, where R is an aromatic substituent, especially 4-methylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, and X is halogen, preferably iodine, chlorine or bromine, with diethyl fumarate, i.e. a compound of general formula 3. The condensation is carried out in an organic solvent, preferably an aliphatic alcohol, especially ethyl, propyl, isopropyl, butyl or dimethylformamide, at the boiling point of the solvent for a period of 1-7 hours, using a molar ratio of the substrates of 1:1, in the presence of basic substances binding the evolved hydrogen halide, preferably in the presence of triethylamine, pyridine, alkali metal alkoxides, sodium or potassium carbonate. After the reaction is completed, the precipitate is separated from the solvent and washed with water or alcohol to remove salts containing chemically bound hydrogen halide, and then, after separating the solution, the precipitate is crystallized from an organic solvent, preferably methyl alcohol, isopropyl alcohol, dimethylformamide or from a mixture of polar solvents: protic, preferably methyl alcohol, isopropyl alcohol and aprotic, preferably dimethylformamide, in a volume ratio of 1:1 to 4:1.

The new compounds obtained by the method according to the invention have pharmacological activity, especially antimicrobial activity.

Example 1:

6.36 g (0.02 mol) of 1-(4'-methylphenyl)-imidazolidin-2-one hydrazone hydroiodide, 3.44 g (0.02 mol) of diethyl fumarate, 2 ml of triethylamine, and 30 ml of n-butanol were placed in a 100 ml round-bottomed flask equipped with a reflux condenser and a mechanical stirrer and heated for 7 hours at the boiling point of the solvent. After cooling, the separated precipitate was filtered off and washed with cold methanol. The precipitate was recrystallized from a mixture of methyl alcohol and DMF in a 1:2 volume ratio. 4.2 g (66.4% yield) of 8-(4'-methylphenyl)-2H-3,4,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazine-4-oxo-3-acetic acid methyl ester was obtained, melting point 142-4°C.

^1H NMR spectrum (δ, ppm, DMSO-d ₆ vs. TMS): 1.19 (t, 3H, CH ₂ CH ₃ ); 2.25 (s, 3H, CH ₃ ); 2.61-2.75 (m, 2H, CH ₂ COOC ₂ H ₅ ); 3.61-4.11 (m, 1H, CH, 4H, 2CH ₂ , 2H, CH ₂ CH ₃ ); 6/09 (s, 1H,NH); 7.13 (d, 2H,CHArom.); 7.52 (d, 2H, CH aroma)

Elemental analysis for the formula C16H20N4O3 (mol. 316.36)

Calculated %C = 60.75 %H = 6.37 %N = 17.71

Marked %C = 60.87 %H = 6.41 %N = 17.76

Example 2:

Proceeding analogously to example 1, 1-(4'-methoxyphenyl)-imidazolidine-2-one hydrazone hydroiodide and diethyl fumarate were used in the reaction to obtain 4.15 g (62.4% yield) of 8-(4'-methoxyphenyl)-2H-3,4,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazine-4-oxo-3-acetic acid methyl ester with a melting point of 133-4°C

^1H NMR spectrum (δ, ppm, DMSO-d ₆ vs. TMS): 1.19 (t, 3H, CH ₂ CH ₃ ); 2.61-2.77 (m, 2H, CH ₂ COOC ₂ H ₅ ); 3.72-4.11 (m, 3H, OCH ₃ , 4H, 2CH ₂ , 1H, CH, 2H, CH ₂ CH ₃ ); 6/04 (s, 1H, NH); 6.92 (d, 2H, CHarom.); 7.55 (d, 2H, CH aroma)

Elemental analysis for the formula C16H20N4O4 (mw 332.36)

Calculated %C = 57.82 %H-6.07 %N= 16.86

Marked %C = 57.77 %H = 6.12 %N= 16.94

PL 196 516 B1

Example 3:

Proceeding analogously to example 1, 1-(3'-chlorophenyl)-imidazolidine-2-one hydrazone hydroiodide and diethyl fumarate were used in the reaction to obtain 4.1 g (60.3% yield) of 8-(3'-chlorophenyl)-2H-3,4,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazine-4-oxo-3-acetic acid methyl ester with a melting point of 104-5°C.

^1H NMR spectrum (δ, ppm, DMSO-d ₆ vs. TMS): 1.19 (t, 3H, CH ₂ CH ₃ ); 2.61-2.79 (m, 2H, CH ₂ COOC ₂ H ₅ ); 3.78-4.13 (m, 4H, 2CH ₂ , 1H, CH, 2H, CH ₂ CH ₃ ); 6.22 (s, 1H, NH); 6.98-7.99 (m, 4H, CHarom ^.)

Elemental analysis for the formula C15H17ClN4O3 (mw 336.78)

Calculated %C = 53.50 %H = 5.09 %N = 16.64 %Cl = 10.53

Marked %C = 53.64 %H = 5.14 %N = 16.72 %Cl = 10.49

Example 4:

Proceeding analogously to Example 1, 1-(4'-chlorophenyl)-imidazolidine-2-one hydrazone hydroiodide and diethyl fumarate were used in the reaction to obtain 4.3 g (64.2% yield) of 8-(4'-chlorophenyl)-2H-3,4,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazine-4-oxo-3-acetic acid methyl ester with a melting point of 153-4°C.

^1H NMR spectrum (δ, ppm, DMSO-d ₆ vs. TMS): 1.19 (t, 3H, CH ₂ CH ₃ ); 2.6-2.78 (m, 2H, CH ₂ COOC ₂ H ₅ ); 3.79-4.12 (m, 4H, 2CH ₂ , 1H, CH, 2H, CH ₂ CH ₃ ); 6.19 (s, 1H, NH); 7.37 (d, 2H, CHarom.); 7.67 (d, 2H, CH aroma)

Elemental analysis for the formula C15H17ClN4O3 (mw 336.78)

Calculated %C = 53.50 %H = 5.09 %N= 16.64 %Cl = 10.53

Marked %C = 53.55 %H = 5.13 %N= 16.59 %Cl = 10.59

Claims (2)

Patent claims 1. New ethyl esters of 8-aryl-2H-3,4,6,7-tetrahydroimidazo [2,1-c] [1,2,4] triazine-4-oxo-3-acetic acids of the general formula 1, in wherein R is an aromatic substituent, preferably 4-methylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl. 2. The method of obtaining new ethyl esters of 8-aryl-2H-3,4,6,7-tetrahydroimidazo [2,1-c] [1,2,4] triazine-4-oxo-3-acetic acids of general formula 1 wherein R is an aromatic substituent, preferably 4-methylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, characterized in that the compound of general formula 2 in which R is as defined above and X is halogen, preferably iodine, chlorine or bromine is subjected to a condensation reaction with diethyl fumarate, i.e. a compound of general formula 3 in the presence of basic substances which bind the evolving hydrogen halide, preferably in the presence of triethylamine, pyridine, alkali metal alkoxides, sodium or potassium carbonate, and the process is carried out in an organic solvent , preferably of an aliphatic alcohol, especially ethyl, propyl, isopropyl, butyl or dimethylformamide, at the boiling point of the solvent for 1-7 hours, using a molar ratio of the reactants of 1: 1, and after completion of the reaction, the precipitate is isolated After separation from the solvent, it is washed with water or alcohol, and then crystallized from an organic solvent, preferably from methyl, isopropyl alcohol, dimethylformamide or from a mixture of polar solvents: protic, preferably methyl, isopropyl and aprotic alcohol, preferably dimethylformamide in a volume ratio of 1: 1 to 4: 1.